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Open Access

Abstract

Shortwave infrared radiation (SWIR) is the portion of the electromagnetic spectrum from approximately 900 nm to 2500 nm. Recent advances in imaging systems have expanded the application of SWIR emitters from traditional fields in materials science to biomedical imaging, and the new detectors in SWIR opened an opportunity of deep tissue imaging. Achieving deep photon penetration while maintaining high resolution is one of the main objectives and challenges in bioimaging used for the investigation of diverse processes in living organisms. The application of SWIR emitters in biological settings is, however, hampered by low quantum efficiency. So far, photoluminescent properties in the SWIR region have not been improved by extending concepts that have been developed for the visible (400–650 nm) and near-infrared (NIR, 700–900 nm) wavelengths, which indicates that the governing behavior is fundamentally different in the SWIR. The focus of this minireview is to examine the mechanisms behind the low efficiency of SWIR emitters as well as to highlight the progress in their design for biological applications. Several common mechanisms will be considered in this review: (a) the effect of the energy gap between the excited and ground state on the quantum efficiency, (b) the coupling of the excited electronic states in SWIR emitters to vibrational states in the surrounding matrix, and (c) the role of environment in quenching the excited states. General strategies to improve the quantum yields for a diverse type of SWIR emitters will be also presented.

1 Background

Achieving deep photon penetration is one of the main objectives in bioimaging with optical systems. Rapid deep-tissue imaging has historically been performed using ionizing radiation, typically X-rays or γ-rays. However, ionizing radiation poses a risk to biological tissue and only addresses anatomical alterations. Thus, low energy photons are preferred. The use of visible light is convenient but only feasible for superficial tissues, such as skin, due to strong absorption and scattering from tissue components.

In the last 20 years, near-infrared (NIR, 700–900 nm) fluorescent contrast agents, small molecules, and nanoparticles for in vivo imaging of live tissue have dominated the preclinical and clinical research landscape [1], [2], [3], [4], [5], [6]. Reduced scattering by the tissue; low absorption from tissue endogenous chromophores such as water, lipids, proteins, and hemoglobin; and negligible autofluorescence has led to the selection of the NIR range as an optical window. Along with the availability of conventional silicon-based NIR enhanced CCD cameras and inexpensive light sources (i.e. 785 nm lasers), research has led to an explosion of publications, patents, and reviews from many laboratories related to NIR contrast agents [7], [8], [9], [10] including from our group [11], [12], [13]. This explosion grew out of a well-developed understanding of the chemistry and biology of NIR fluorophores. From organic molecules to nanoparticles, early acceptance of NIR technology by the biological community has also led to the commercial development and clinical trials of many types of contrast agents. Today, more than 20 NIR contrast agents, which can be either free or conjugated to monoclonal antibodies, have been used in clinical trials, and dedicated imaging systems have emerged such as FLARE [14], NIR goggles [15], Spy Elite (Novadaq) [16], da Vinci (Intuitive Surgical) [17] for clinical diagnostics, as well as image- and robotic-guided surgeries [18], [19]. The field is well established.

Despite the progress in the NIR technology, the major drawback of shallow tissue penetration has remained the limiting factor and restricts applications to primarily small animal preclinical models (mice, small rats) [20], [21] or to assessing subcutaneous (breast, skin) [22], [23] and optically accessible tissues (i.e. esophagus, colon) [24], [25] in humans. Although not as strong in the NIR as under visible light, scattering continues to be the key obstacle in deep tissue imaging. Thus, deeper tissue penetration requires using wavelengths greater than 900 nm.

The importance of imaging in shortwave infrared radiation (SWIR) comes from the requirement to provide diagnostic tools for preclinical studies in larger animals (i.e. rabbits, dogs, and pigs, as their anatomy and physiology are more similar to human beings than rodents) [26], [27]. The importance of SWIR imaging also stems from its potential translatability to humans to replace or complement high-energy imaging modalities [such as X-ray, positron emission tomography (PET), or single-photon emission computed tomography (SPECT)].

Imaging solutions that go further into the red region than 900 nm, such as SWIR, or extended NIR (exNIR) have long been proven difficult to develop, primarily due to the lack of sensitive detectors. Commonly utilized silicon-based sensors are inefficient beyond 1100 nm, resulting in low signal [28]. Beyond 1100 nm, the Si material becomes transparent to photons as the corresponding photon energy drops below the band gap energy of this semiconducting material [29]. Operating at longer wavelengths requires coating the Si sensor with a wavelength shifting phosphor, which reduces quantum efficiency. Detectors based on germanium (Ge), indium antimonide (InSb), or mercury cadmium telluride (HgCdTe) are more sensitive but still suffer from low quantum efficiency in the SWIR range [30]. Thankfully, indium gallium arsenide (InGaAs) sensors, with their high quantum efficiency in the 900–1600 nm range, have appeared. These sensors were used mostly for military applications, such as to minimize the scattering effect of clouds or fog, a problem similar to the in vivo imaging challenge.

The development of InGaAs-based diode array detectors, research grade 2D cameras, and SWIR light sources (conventional quartz bulbs, temperature stabilized LEDs, laser diodes, and supercontinuum lasers [31]) sparked interest in using this technology in biology, and soon researchers recognized that in addition to the NIR, there were other optical windows in the SWIR [31], [32], [33], [34], [35], [36], [37]. Using the new detectors, several groups have demonstrated significantly higher transparency of tissue in SWIR compared to the traditional NIR range, with some of the most prominent bands of transparency at 1300 and 1550 nm [35], [37] (Figure 1). Even higher transparency may be possible at longer wavelengths (i.e. 1800 nm and 2200 nm) [36] where most of the current InGaAs detectors have low sensitivity but can rely on InSb imaging detectors for longer wavelengths.

Figure 1:

Transparency of biological tissue in SWIR.

The metric is based on a spatial contrast of Michelson (with permission [37]).

Further steps toward the development of SWIR-based optical imaging will require more efficient contrast agents. To date, the development of biological imaging techniques utilizing absorption and emission in SWIR (SWIR→SWIR) has been limited, primarily because of the lack of efficient biocompatible emitters in this range [38]. Most of the organic SWIR dyes and many types of nanomaterials that have been developed for lasers and the telecommunication industry [39] were unsuitable for SWIR imaging due to their low (<0.1%) quantum efficiency, poor water solubility, and potential systemic toxicity. To be considered in biology, early materials, such as polymethine dyes, carbon nanotubes, quantum dots, and upconverting nanoparticles, required some sophisticated modifications to ensure sufficient bioavailability, excretion, and low toxicity. One of the successful examples is shown in Figure 2 [40]. However, once modified, these materials demonstrated even lower quantum yield in aqueous media and poor imaging performance. The low quantum yield necessitated long light exposures, which are potentially damaging to tissue.

Figure 2:

Imaging of deep tissue using a dual NIR-SWIR probe based on the dye IR800CW attached to single-walled carbon nanotubes (SWCNs): (A) C57Bl/6 mouse head with hair removed; (B) fluorescent images of the same mouse at 850–900 nm, (C) 1300–1400 nm.

Red arrows point to specific locations in the brain that can be resolved (with permission from [40]).

Over the last 10 years, the photoluminescent properties of contrast agents for biological agents in the SWIR have been substantially improved. However, they are still far below the level of visible contrast agents with 80–100% quantum efficiency. It has been realized that the governing behavior is fundamentally different in the SWIR compared to the visible region. Understanding the mechanism of low efficiency in the SWIR and demonstrating progress and potential ways to improve the signal is the focus of this minireview.

2 Mechanisms of low emission

Significant efforts have been put forth for both understanding the origins of low efficiency in current SWIR emitters and developing methods to minimize quenching effects. Out of the many pathways behind the quenching of SWIR emission, we will consider the common mechanisms that are shared by several types of contrast agents. These mechanisms include (a) the effect of the energy gap between the excited and ground states, (b) the presence of vibrational states in the surrounding matrix and their coupling with the excited electronic states, and (c) the role of environment on emitter stability and brightness. Individual specific mechanisms, such as those caused by structural defects (i.e. in SWCNs [41]), will be mentioned only briefly.

2.1 Energy gap law

The energy gap law is a fundamental constraint that states that radiationless transitions at longer wavelengths increase due to vibrational overlap between the ground and excited states [42] (Figure 3). These overlaps cause a decrease in the photoluminescent efficiency of organic and organometallic fluorophores [43] and also seem to be unavoidable in nanocrystals. This law radically restricts the number of luminescent dyes beyond 1000 nm where the overlap is almost inevitable.

Experimental verification of the energy gap law was established several decades ago, primarily for organic dye molecules emitting in the visible and NIR range. Those include aromatic hydrocarbons [44]; linear polyenes, including carotenoids [45]; organometallic complexes [46]; and large polymeric molecules [47]. In many of these studies, a logarithmic dependence of the non-radiative constant upon the energy gap was demonstrated. The non-radiative decay rate (knr) increases exponentially with decreasing energy separation between the excited and the ground states [48].

A critical aspect of the energy gap law is the mechanism of energy transfer from the excited state. It has been agreed in general that the excited state serves as a donor that provides energy to the vibrational modes of the acceptors within the same molecule or nearby solvent molecules. However, questions about the nature of the acceptors remain largely under discussion. In fact, there is an unsettled debate over whether the critical “accepting” modes (the vibrational modes into which the majority of the excited-state energy is disposed) is C-H or C-C stretching in character. Are there solvent molecules involved? For organic molecules, the experimental results demonstrate that C-C stretching modes play a major, if not the dominant, role in the process [49].

2.2 The nature of vibrational modes in tissue

The excitation energy of the SWIR emitter might be transferred radiatively or non-radiatively to the tissue components. In the radiative process, the emitted photons are reabsorbed by the tissue through the overlap between the emission band of the emitter and the absorption bands of the tissue components. The efficiency of this process depends upon the wavelength of emission and thickness of the tissue. In the non-radiative pathway, the energy dissipation occurs via Förster resonance energy transfer (FRET) without emitting a photon. Because of the short, nanometer-range nature of this effect, the process is primarily governed by the nearest layer of ligands or tissue molecules through their absorption bands.

Absorption bands seen in SWIR in biological tissue components such as water, lipids, proteins, etc. (Figure 4) are the overtones and combination bands of their corresponding fundamental vibrations (tones). The overtone and combination bands are considerably blue-shifted with respect to the tones. The latter are typically observed at mid-infrared (400–4000 cm−1 or 2500–25,000 nm) by IR or Raman spectroscopy. Overtone and combination bands are due to the anharmonicity of the vibration that is the deviation from an ideal harmonic oscillator, such as seen in a bond with two identical atoms. The anharmonicity increases when the bond connects atoms with dramatically different masses, such as in the case of X-H bonds where X is C, O, or N. Because of the anharmonicity of tissue components, the SWIR range is dominated by signals from bonds involving hydrogen atoms such as O-H (water, carbohydrates), C-H (lipids), and N-H (proteins).

The radiative energy transfer or photon reabsorption cannot be avoided, as the emitter in the deep tissue is surrounded by a large number of tissue molecules. The non-radiative process, however, can be efficiently controlled as was first proposed and demonstrated by Guyot-Sionnest et al. [50] and later confirmed by Aharoni et al. [51]. In their seminal paper, Guyot-Sionnest et al. have demonstrated that the direct near-field energy transfer of the electronic excitation to vibrational absorption by ligand or matrix is a predictable quantifiable effect; it is fast and applies to any transition [50]. For example, the non-radiative recombination of excitons, defined as bound electron-hole pairs, in quantum dots results from coupling to C-H vibrations in the surface-bound ligands, which have characteristic frequencies in the wavelength region of interest. Placing an inorganic spacer transparent to SWIR photons or modifying the surface ligands is an example of promising strategies to minimize the probability of non-radiative de-excitation (vide infra).

2.3 Role of vibrational modes in quenching of SWIR emitters

The mechanisms by which photoexcitations are coupled to vibrational modes are graphically summarized by Figure 5. The accepted opinion is that a resonant energy transfer mechanism, akin to Förster energy transfer, is the process by which the exciton couples to ligand vibrations (Figure 5A) [50], [51], [52], [53]. For quantum dots, it has been proposed that the energy transfer proceeds via polaron states formed by strong coupling of vibrational modes to surface trap states (Figure 5B) [54]. In our opinion, coupling of photoexcitations to vibrational states is one of the primary causes of low quantum yield. This hypothesis is consistent with the experimental observations of a number of researchers [50], [51], [52], [53], [54], [55], [56], [57]. For example, InAs nanocrystals with peak emission at 1200 nm showed significantly higher efficiency in halogenated solvent compared to toluene [51]. In the range of the C-H vibrations (1150–1200 nm), the photoluminescence lifetime was approximately three times longer in the halogenated solvent compared to toluene, indicating that excitons were coupled more strongly to C-H stretch modes [51]. In another example, when HgTe nanocrystals emitting at 1060 nm were transferred from H2O to D2O, the quantum yield increased from 5% to 20% [54].

Figure 5:

Exciton relaxation pathways in quantum dots photoluminescent in the SWIR.

2.4 Other mechanisms affecting quantum efficiency

Solvent molecules might stabilize or destabilize the excited states of SWIR emitters. For example, polymethine dye molecules are known to have high sensitivity to solvent polarity, which significantly affects quantum efficiency [58], [59]. Considering that the SWIR absorption bands in polymethine dyes arise from electronic transition involving the π electrons along the polymethine chain, the cations in the ground state of the polymethine dyes resonate between two limiting canonical structures. Based on NMR and crystallography studies of NIR dyes, the ground state of the cyanines are predominantly in all-trans configurations [60], [61]. In the excited state, the bond order lowers and reduces the electron density in the double bonds along the polymethine chain, making the molecule more sensitive to the surrounding molecules and ions.

The change in bond order facilitates vibrational rotations and allows the molecule to twist during its lifetime in the excited state. The twisted conformation is likely to undergo trans-cis isomerization, leading to non-radiative decay. A polar medium facilitates trans-cis transformation, effectively decreasing the quantum efficiency, while a non-polar environment stabilizes the excited state, thereby increasing the quantum yield as well as fluorescence lifetime and photostability. Formation of a microenvironment (polymeric or silica) around the emitter is a known strategy to increase the quantum efficiency of polymethine dyes and has been explored in many NIR contrast agents [62], [63].

2.5 Strategies to decrease quenching

Reabsorption of photons by the tissue absorbers cannot be eliminated or even minimized and is entirely dependent on the tissue thickness. In contrast, non-radiative quenching can be effectively controlled through the architecture of the ligands surrounding the emitter. The partial contribution from each of the pathways is difficult to evaluate, but based on published work, we believe that non-radiative emission dominates the quenching process. Thus, eliminating non-radiative quenching might significantly increase quantum efficiency of the contrast agent.

A set of rules to minimize the effect of quenching of the emitter from the media or ligands was originally established by Hasegawa et al. for SWIR emitting lanthanides [64] but can also be expanded to other classes of SWIR emitters. The rules suggest to (i) avoid hydrogen-rich solvent molecules in the first coordination sphere; (ii) eliminate O-H groups around the emitting core, as these groups are the most efficient quenchers; and (iii) minimize the presence of C-H groups. Although the effects of C-H oscillators are smaller than those of O-H, C-H bonds are abundant in the biological media. Some of the successful examples of using these strategies are based on replacing hydrogen atoms with deuterium or fluorine.

Deuteration or fluorination of ligands coordinating SWIR emitters has been demonstrated in a number of studies, primarily in lanthanides. As deuterium is twice as heavy as hydrogen, such substitution (from C-H to C-D, and O-H to O-D) decreases the strength of the oscillator. This decrease leads to a decline in absorbance band intensities from the vibrational state and diminishes the influence of the overtones on emission. Hence, deuteration of ligands has been demonstrated to increase the quantum yield in a number of SWIR emitting complexes, including Er3+, Nd3+, and Yt3+ emitters [65], [66]. Fluorine is even larger than deuterium, so the effect is stronger and is considered to be more efficient than deuteration [67]. Complete fluorination might be quite complex and require substantial synthetic efforts; instead, partial fluorination can be used. This partial fluorination of ligands has led to a significant improvement of the quantum efficiency of Er3+ complexes emitting at 1535 nm [68], [69].

Encapsulation of the emitter within an inorganic matrix transparent to SWIR photons follows the same idea. The matrix shields the emission core by increasing the distance between the donor and the acceptor. Given that energy transfer is inversely proportional to the distance as 1/r6, several nanometers of the layer might be sufficient. Consistent with this idea, PbS quantum dots protected with As2S3 shells showed a significant increase in the quantum efficiency [70].

3 Emitters in SWIR

Today, there are several classes of SWIR emitting dyes and nanomaterials that have been or can potentially be used in SWIR imaging (Figure 6). Reported compounds include cyanine dyes [74], lanthanide complexes [75], Pt complexes [73], certain types of quantum dots [76], small gold nanoparticles [77], and single-walled carbon nanotubes (SWCNTs) [32], [33]. We will briefly describe some of these most common contrast agents while focusing on strategies to improve quantum efficiency.

Schematics of single-walled carbon nanotubes (with permission from [71]), upconverting nanoparticles (with permission from [72]), nanowire formed by self-assembly of a Pt complex (with permission from [73]), and quantum dots.

3.1 Organic dyes

Historically, organic dyes were the first small molecules developed in early 1980s to emit in the SWIR range, primarily as the media for tunable dye-based lasers [78], [79]. Organic dyes that are fluorescent in the SWIR, such as IR-26, IR-1048 or IR-1061, are stable but highly hydrophobic and suffer from extremely low quantum yield – less than 0.05% [52], [80]. In addition to a significant overlap between the excited and ground states (low energy gap) and quenching by vibrational states of solvent molecules, the emission of these dyes is strongly influenced by solvent polarity.

Encapsulation of the hydrophobic SWIR dye IR-1061 into a water-soluble polymer nanoparticle with a hydrophobic cavity has led to a relatively high quantum yield, enabling real-time imaging of hind-limb hemodynamics [81]. A recent development in using organic dyes was achieved with a new SWIR dye, CH1055, conjugated to PEG for facilitated bioavailability and excretion [82].

3.2 Single-walled carbon nanotubes

SWCNTs are SWIR-emitting materials that have been extensively investigated forsensing in biological media in vitro [83], [84] and in vivo [32], [85]. Due to their sharp multiple SWIR spectral features across a broad bandwidth from 800 to 1600 nm, SWCNTs also showed the potential for in vivo hyperspectral imaging [86], [87]. However, photon-conversion efficiency of SWCNTs is relatively low (<0.1%) [88], which makes SWCNTs suboptimal for demanding bioimaging applications.

Theoretical and experimental studies suggest that carbon nanotube photoluminescence is inefficient because of low-lying dark excitons that enhance non-radiative transmission [71], [89]. Various structural defects that develop during their synthesis or processing can accumulate over the relatively long length (100–1000 nm) of the nanotubes [41], [90]. Studying the decay rate of the fluorescence from individual SWCNTs, Wang et al. suggested that the low fluorescence quantum yield is controlled by quenching from the structural defects [41]. The structural defects can also react with oxygen to form a hydroperoxide carbocation in a process known as hole doping [91], which further decreases the quantum yield. Nanotube aggregation has also been reported as a cause of quenching [92].

Several strategies have been published to improve the quantum efficiency of nanotubes. Minimizing the oxidative defects by hole passivation with reducing agents [93] and oxygen-excluding surfactants [94] has improved the quantum yield. Purification of the nanotubes through gradient centrifugation and minimizing the aggregation has also been fruitful for increasing the efficiency to 20% [94]. Another breakthrough came from covalent functionalization of SWCNTs with a controlled number of aryl functional groups that produced a new and bright photoluminescence peak through introduction of a bright defect state [95].

3.3 Lanthanide nanoparticles

Lanthanide-based nanomaterials have [96] emerged relatively recently for optical imaging due to their high stability and low toxicity [97]. The most common lanthanide-based nanoparticles are based on the photon upconversion effect, in which at least two incident photons of relatively low energy are absorbed and converted into one emitted photon with higher energy [98]. Typical upconverting nanoparticles (UCNPs) are oxides or fluorides, i.e. NaYF4 doped with lanthanides, such as Yb3+ ions that work as sensitizers and co-doped with Er3+ or Tm3+ ions that serve as emitters (activators). In the most common designs of UCNP NaYF4:Yb/Er, Tm, the excitation occurs at ca. 980 nm due to the absorption by Yb3+. The long-lived metastable energy state of the excited Yb-ions allows additional photons to be absorbed. The absorbed multiphoton energy is then transferred from the sensitizer to the activator, resulting in emission at shorter wavelengths. For example, Tm3+ emits at 474 nm and 798 nm [96] while Er3+ emits at 410, 520, 540, and 660 nm [96].

Ideally, deep tissue imaging requires excitation and emission in SWIR (SWIR→SWIR). In reality, this is difficult to achieve with the currently developed UCNPs. The excitation of most UCPNs occurs in SWIR (980 nm), but their emission lies in the Vis or NIR range (SWIR→Vis, NIR). Similarly structured nanoparticles, such as lanthanide-based downconverting nanoparticles (DCNPs), absorb in the visible range and emit in the SWIR (Vis →SWIR). For example, LaF3 nanoparticles doped with Nd3+, Ho3+, or Er3+ emit at 1330, 1450, and 1525 nm correspondingly but require an excitation with a 513-nm laser to achieve good signal [99], [100].

Addressing this challenge, photon downconversion has been accomplished using a NIR laser (802 nm) to achieve NIR→SWIR [101]. Recently Kamimuro et al. used PEGylated Y2O3:Yb, Er nanoparticles to show a strong signal at 1550 nm in vivo upon irradiation with a 980-nm laser, thus realizing SWIR→SWIR imaging [102].Furthermore, Naczynski et al. developed a library of rare earth nanoreporters with tunable, discrete SWIR emission over the broad range of 1000–2300 nm.

The luminescence efficiency of UCNPs and DCNPs emitting in SWIR is generally low. Several strategies have been devised to improve the quantum efficiency. To suppress the vibrational quenching caused by the O-H groups from water on the surfaces of NdF3 nanoparticles, they were coated with silica [103]. This treatment led to a 1.6 times higher intensity than that of bare NdF3. In a similar strategy, Chen et al. grew a thin layer of NaGdF4 shells on top of NaGdF4:Nd3+ of nanocrystals to prepare highly efficient DCNPs with an absolute quantum yield of 40% [104].

3.4 Quantum dots

Synthetic protocols for known materials that have band gaps appropriate for emission in the SWIR were established a relatively long time ago [105], [106]. Today, there are quantum dots composed of different types of semiconductors including InAs and InP, PbSe and PbS, HgTe, Ag2S and Ag2Se, CuInS2, and CuInSe2. Photoluminescent semiconductor nanocrystals are in general much brighter than other SWIR emitters such as dyes, SWCNTs and DCNPs, in which their brightness, in part, stems from high molar absorptivities. In the context of bioimaging applications, the quantum yield values that have been demonstrated to date are still rather low – less than 10% at a peak wavelength of 1550 nm when measured in an inert, air-free environment.

A major problem in using SWIR quantum dots in a biological setting is their notorious instability in aqueous media. Virtually all known quantum dots materials degrade in the presence of water and air [107], [108]. For example, PbS and PbSe quantum dots are prone to oxidation and other reactions (i.e. etching, photobleaching) resulting in the loss of emission [109], [110]. Thus, the principal challenge is to develop a robust shell that protects the emitting core. While for the visible emitting quantum dots composed of CdSe, the growth of a passivating shell such as CdS/ZnS has been well established, with the quantum yield reaching unity [111], this approach has been proven to be more difficult for SWIR emitters. There are only a handful reports that have been able to show the application of SWIR quantum dots in bioimaging [112].

Oxide coatings on quantum dots are known to exhibit excellent chemical stability that can be applied to protect the core [115]. A key challenge with metal oxide coatings is to ensure they are free from OH groups, which are expected to exacerbate vibrational PL quenching. Addressing this challenge, Yin et al. developed a high-precision method of coating quantum dots using an atomic layer deposition technique to improve the photoluminescence stability [116]. Although the method has been demonstrated on visible quantum dots, it could potentially be expanded to SWIR emitters as well.

4 Concluding remarks

The last decade saw the emergence of SWIR emitting small molecules and nanoparticles that have great potential in the field of bioimaging. A great number of synthetic procedures have been developed; however, for most of the compounds, the quantum efficiency remains low. Hence, significant effort has been spent to develop and deploy biocompatible small molecules and nanomaterials that are bright in the SWIR. Protection of the emitters from aggressive biological media and/or minimizing energy transfer from the emitter to tissue chromophores in order to retain high quantum efficiency presents a significant challenge. Other critical barriers that limit biological applications include (i) relatively low reproducibility and scalability; (ii) poor long-term stability in aqueous media, buffers, and biological media; (iii) difficulty in attaching targeting groups; (iv) potential immunogenicity; and (v) limited clinical translation that requires no toxic metals in the formulation regardless of the product stability.

Given that the synthesis of bright emitters, especially nanoparticles, involves a complex compositional space, computational approaches, such as those based on machine learning and data mining, may be of great value in the search for new material systems. In the field of emitters, such an approach has the potential to quickly predict the brightest stable and non-toxic nanoparticles with the desired properties as a function of size, composition, and heterostructure. Accurate modeling of the photophysics and photochemistry of SWIR nanoemitters will facilitate and accelerate the synthetic procedures to identify high-performance, nontoxic materials.

Overall, the progress in the development of SWIR emitters has been dramatic and exciting. Further progress in this field will require innovative strategies to not only enhance the radiative-transition rate of SWIR-emitting species but also make them highly biocompatible.

Acknowledgments

We thank NCI/NIH CA198419 (MB), NSF Research Infrastructure Improvement Award #IIA-1355406 (MB), for the financial support in writing this review. We also thank William Buhro (Washington University) for the discussion and Sharon Bloch for editing the manuscript.

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